Process for preparing nicotinamide



United States Patent 3,450,706 PROCESS FOR PREPARING NICOTINAMIDE NormanL. Wendler, Summit, David Taub, Metuchen, and Chan Hwa Kuo, SouthPlainfield, N.J., assignors to Merck & Co., Inc., Rahway, N.J., acorporation of New Jersey No Drawing. Filed June 3, 1966, Ser. No.554,963 Int. Cl. C07d 31/44, 29/30 US. Cl. 260-295.5 3 Claims ABSTRACTOF THE DISCLOSURE Nicotinamide is prepared from 1-acyl-3-cyano-4-amino-1,2,5,6-tetrahydropyridine or 1-acyl-3-cyano-4-ketohexahydropyridine byreaction with an acid and tertiary butyl ions to formN-t-butyl-1-acyl-4-ketohexahydronicotinamide which is subsequentlyreduced and then acylated to effect reduction of the keto group at the 4position to a hydroxy substituent and then to an acyloxy group. The thusformed N-t-butyl-1-acyl-4-acyloxyhexahydronicotinamide is then treatedwith a noble metal to effect the simultaneous removal of thesubstituents in the 1,4 position and aromatization of the ring to formN-t-buyl-nicotinamide, the latter which upon hydrolysis yieldsnicotinamide.

This invention relates to processes and intermediates useful forpreparing nicotinamide. More particularly, it is concerned withprocesses for producing nicotinamide from 3-cyano-4-amino-1,2,5,6-tetrahydropyridine and new pyridine compounds useful asintermediates in these processes.

Methods used for the manufacture of nicotinamide employ as the startingcompound products containing a pyridine ring or a substituted pyridinering. In most cases, the nicotinamide is prepared by the degradation ofa more complex compound to nicotinic acid and, subsequently, convertingthe acid to the amide by known methods. These known methods suffer fromthe disadvantages that the reactions are difficult to carry out on acommercial scale and that from time to time the starting pyridinecompounds are in short supply.

It is an object of the present invention to provide new processes forproducing nicotinamide. It is a further object to provide processes forproducing nicotinamide starting with3-cyano-4-amino-1,2,5,6-tetrahydropyridine. Another object is to provideprocesses for the preparation ofN-t-butyl-1-acyl-4-ketohexahydronicotinamide,N-tbutyl-1-acyl-4-hydroxyhexahydronicotinamide, andN-tbutyl-1-acyl-4-acyloxyhexahydronicotinamide and methods forconverting these compounds to nicotinamide. Other objects will beapparent from the detailed description of this invention hereinafterprovided.

The processes for preparing nicotinamide in accordance with ourinvention can be depicted structurally as follows:

o ONHC (CH3):

N n ON (3) N is OH 0H f f CONHO(OHa)a CONHC(CH3)3 4 KN R 1'1 CONHC(0H3): CONH1 wherein R is an acyl group such as lower alkanoyl.

In accordance with one embodiment of this invention, 1-acyl-3-cyauo-4-amino-l,2,5,6-tetrahydropyridine or l-acyl-3cyano-4-ketohexahydropyridine is reacted with tertiary butyl ions inthe presence of a strong acid to produceN-tbutyl-1-acyl-4-ketohexahydronicotinamide (3), which is then reducedto obtain N-t-butyl-l-acyl-4-hydroxyhexahydronicotinamide (4). Thelatter compound is then acylated to produce the corresponding 4-acyloxycompound (5), which, on reaction with a noble metal, is converted toN-t-butylnicotinamide (6) This compound, upon hydrolysis of the tertiarybutyl group, affords nicotinamide.

In accordance with the first step of the above-described process, 1 acyl3-cyano-4-amino-1,2,5,6-tetrahydropyridine orl-acyl-3-cyano-4-ketohexahydropyridine is reacted in the presence of astrong acid with a source of tertiary butyl ions to produceN-t-butyl-1-acyl-4-ketohexahydronicotinamide. In carrying out this stepof our process, we prefer to use a l-acyl compound wherein the acylgroup is lower alkanoyl, since such compounds are readily prepared andresult in maximum yields of the desired product under optimumconditions. This step of our process is most conveniently effected byintimately contacting the starting materials with isobutylene in thepresence of a strong acid, such as sulfuric acid in an acetic acidmedium. Other strong non-oxidizing mineral acids, such as hydrochloricand hydrobromic acids, can similarly be used in carrying out thisreaction. The reaction is conveniently effected by dissolving thestar-ting material in acetic acid, adding sulfuric acid to the solution,and then bubbling gaseous isobutylene into the resulting solution. Aftercompletion of the reaction, which is preferably effected at lowtemperatures of about 20 C., the reaction mixture is diluted with waterand concentrated under reduced pressure to remove the tertiary butylalcohol. After removal of the alcohol, the remaining aqueous solution ismade alkaline with sodium carbonate, saturated with salt, and theproduct extracted with a suitable solvent such as ethyl acetate.Evaporation of the resulting extract 3 affords the desiredN-t-buyl-l-lower alkanoyl-4-ketohexahydronicotinamide.

Alternatively, the first step of our process is carried out by reactingthe starting materials with a suitable source of tertiary butyl ions,such as tertiary butyl acetate, in the presence of a strong acid such asperchloric acid. In carrying out this reaction, the starting material,either l-lower alkanoyl-3-cyano-4-amino-1,2,5,6-tetrahydropyridine or 1-lower alkanoyl-3-cyano-4-ketohexahydropyridine, is suspended in tertiarybutyl acetate and 70% perchloric acid added thereto while maintainingthe temperature at about 10 C. After completion of the reaction, theproduct is recovered using procedures as described above.

The N-t-butyl-l-acyl-4-ketohexahydronicotinamide is reduced to thecorresponding 4-hydroxy compound by either chemical or catalyticreduction procedures. Thus, the product can be reduced by reaction witha suitable reducing agent such as an alkali metal borohydride, forexample, sodium borohydride. Alternatively, the process is effected byintimately contacting the 4-keto compound in solution with hydrogen inthe presence of a suitable noble metal hydrogenation catalyst such aspalladium or reduced platinum oxide.

The resulting 4-hydroxy compound is then acylated in the next step ofour process to produce the corresponding 4-acyloxy compound. Thus, theproduct of the reduction reaction, which may be either the cis or thetrans isomer, is intimately contacted with an acylating agent,preferably a lower alkanoyl acylating agent, to produce thecorresponding 4-acyloxy compound. For example, the acylation can becarried out by intimately contacting the 4-hydroxy compound with a loweralkanoyl anhydride or halide in the presence of an acid-binding agent.Although any of the various lower alkanoyl anhydrides or acid halidescan be used for this purpose, we prefer to effect the reaction utilizingacetic anhydride or acetyl chloride, since these products are mostreadily available.

In the next step of our process, the N-t-butyl-l-acyl-4-acyloxyhexahydronicotinamide is heated in contact with a noble metal toeifect simultaneously the aromatization of the pyridine ring and theremoval of the substituents at positions 1 and 4. This dehydrogenationreaction is effected by heating the substituted hexahydronicotinamidecompound in intimate contact with a noble metal such as finely-dividedpaladium, platinum, ruthenium, rhodium, osmium, or iridium or one ofthese noble metals supported on a suitable carrier such as carbon. Themetal and the hexahydronicotinamide compound are intimately mixed attemperatures of between IUD-300 C. for a period of 1-10 hours to producethe desired N-t-butylnicotinamide. In the preferred method of opertion,the compound to be dehydrogenated is disolved in an inert solvent suchas a high-boiling ether or hydrocarbon having a boiling point of betweenabout l300 C. The noble metal is added and the resulting reactionmixture is heated for sufiicient time to complete the dehydrogenation.Suitable solvents which can be used in this process include saturatedpolycyclic hydrocarbons such as decalin or stilbene or a highboilingether such as diphenyl ether. The amount of noble metal used in thisdehydrogenation is not critical, and quantities ranging from about 1% toabout 100% based on the weight of the compound being dehydrogenated canbe used, depending upon the particular noble metal and the reactionconditions employed. After the reaction is complete, the product isreadily recovered from the resulting reaction mixture by diluting itwith a suitable solvent, removing the noble metal, and extracting thefiltered reaction mixture with an acidic aqueous solution from which theproduct can then be recovered by extraction with a suitable solventafter the acid solution has been made alkaline.

The N-t-butylnicotinamide so obtained can then be hydrolyzed to producenicotinamide. This is conveniently accomplished by dissolving theN-t-butyl compound in concentrated sulfuric acid and recovering thenicotinamide by diluting the reaction mixture with water, making theresulting solution alkaline, and extracting the nicotinamide with asuitable solvent such as chloroform. Evaporation of the resultingchloroform extract affords the desired nicotinamide.

The following examples are given to illustrate specific methods ofcarrying out the processes of this invention:

EXAMPLE 1 N-t-butyl-l-acetyl-4-ketohexahydronicotinamide To a solutionof 13,2 grams of l-acetyl-3-cyano-4- ketohexahydropyridine in 350 ml. ofacetic acid is added 37 ml. of concentrated sulfuric acid whilemaintaining the reaction mixture at 20 C. To the stirred reactionmixture is added gaseous isobutylene While maintaining the reactionmixture at less than 20 C. for about 1 hour, during which time thevolume of the reaction mixture increases about 96 ml. and the product,N-t-butyl-1-acetyl-4-ketohexahydronicotinamide, is formed. The entirereaction mixture is then maintained for approximately 19 hours at 20 C.and the mixture then diluted with 450 ml. of ice water. The entirereaction mixture is then concentrated under reduced pressure to removet-butyl alcohol while maintaining the temperature at less than 40 C.After removal of the alcohol, the remaining aqueous solution of theproduct is made alkaline with sodium carbonate saturated with sodiumchloride and the product extracted with ethyl acetate. The ethyl acetateextract of product is then washed with sodium chloride solution, dried,and concentrated to yield a yellow, oily residue which crystallizes fromether to provide N-t-butyl-1-acetyl-4-ketohexahydronicotinamide inexcellent yield. M.P. 9698 C., xggP (sh.) 243 mu (E, 720 rgggf 278 111,.

(E, 12,500); V 2.9-2.9s, 5.84, 6.026.2, 6.57

max.

Similarly, l-acetyl-3-cyano-4-amino-1,2,5,6-tetrahydropyridine istreated as above to give the same product.

In similar manner, when other l-acyl derivatives of3-cyano-4-ketohexahydropyridine or 3-cyano-4-amino-1,2,5,6-tetrahydropyridine such as other l-lower alkanoyl compounds, forexample, the l-propionyl, l-butyryl, or the l-hexyl derivatives, arereacted with isobutylene in a mixture of acetic acid and sulfuric acid,the corresponding l-acyl-3-cyano-4-ketohexahydropyridines are obtained.

The l-acetyl-3-cyano-4-ketohexahyd ropyridine used as the startingmaterial in the foregoing example can be prepared as follows:

To a stirred slurry of 32.0 grams of 3-cyano-4-amino-1,2,5,6-tetrahydropyridine in 300 ml. of pyridine is added ml. of aceticanhydride while cooling the reaction mixture to maintain the temperatureat about 30 C. During a period of about 15-20 minutes, the stirredmaterial dissolved in solution gives a light yellow solution and theproduct begins to precipitate. The reaction is allowed to proceed for anadditional 1 /2 hours and the precipitated product is removed byfiltration, washed successively with toluene and ether and air dried togive substantially pure1-acetyl-3-cyano-4-amino-1,2,5,6-tetrahydropyridine, M.P. 174-177 C. Onrecrystallization of the product from acetone, the product exhibits thefollowing characteristics: M.P. 177-178 C.;

mou 3 my (E, 11,600); A???) when in place of the corresponding anhydridethe acid chloride or bromide is utilized as the acylating agent.

A solution of 1 gram of l-acetyl-3-cyano-4-amino-1,2,5,6-tetrahydropyridine in 3 ml. of 2.5 N aqueous hydrochloric acidis prepared and allowed to stand at room temperature (25 C.) forapproximately minutes. The entire reaction mixture is then neutralizedwith aqueous 2.5 N sodium hydroxide solution and concentrated in vacuoleaving the product as a residue. The residual material is flushed withmethanol and toluene to remove impurities and subsequently acidified topH 4 with aqueout 2.5 N hydrochloric acid and again concentrated todryness. The residual partially-pure product is flushed with twoportions of benzene to remove additional impurities and the remainingresidue containing the product is extracted by slurrying with five ml.portions of hot acetone. The acetone solution of product is thenfiltered to remove insoluble, inorganic impurities and the acetatefiltrate containing the product concentrated in vacuo to yieldsubstantially pure l-acetyl-3-cyano-4-ketohexahydropyridine in excellentyield.

EXAMPLE 2 Alternative procedure for preparing N-t-butyl-l-acetyl-4-ketohexahydronicotinamide 5 ml. of 70% perchloric acid is added to astirred suspension of 3.31 grams of1-acetyl-3-cyano-4-ketohexahydropyridine in 38 ml. of t-butyl acetateover a period of about minutes while maintaining the temperature of thereaction mixture at about 10 C. Stirring is continued for approximately17 hours at 20-25 C. and then the entire reaction mixture diluted withcrushed ice and the t-butyl alcohol formed is removed by distillation ofthe reaction mixture under reduced pressure while maintaining thetemperature of the reaction mixture below 40 C. The resulting aqueoussolution of the product is adjusted to pH 910 with aqueous sodiumhydroxide and maintained at room temperature for approximately 3 hours.The entire reaction mixture is then acidified with 2.5 N hydrochloricacid, saturated with salt, and the product extracted with methylenechloride. The methylene chloride extract of the product is then 'washedwith salt water, dried, and concentrated to produce the product in theform of a yellow oil which crystallizes readily from ether diluted witha small amount of acetone. M.P'. 96-98 C.

Similarly, 1-acetyl-3-cyano-4-amino-l,2,5,6-tetrahydropyridine istreated as above to give the same product.

In the same way, other l-acyl derivatives of 3-cyano-4-ketohexahydropyridine such as other lower alkanoyl derivatives, forexample, the l-propionyl, l-butyryl, or the l-hexyl derivatives, can bereacted with t-butyl acetate in the presence of perchloric acid toproduce the corresponding l-acyl derivatives ofN-t-butyl-4-ketohexahydronicotinamide.

EXAMPLE 3 Tr ans-N-t-butyll-acetyl-4-hydroxyhexahydronicotinamide Asolution of 500* mg. of sodium borohydride in 20 ml. of water containing2 drops of 2.5 N sodium hydroxide is added dropwise to a stirredsolution of 2.2 grams of N-t-butyl-1-acetyl-4-ketohexahydronicotinamidein 40 ml. of water. The reaction is maintained at C. for about 2 /2hours with stirring to form the product in excellent yield. The productis recovered by acidification of the reaction mixture with 50% aqueousacetic acid, concentrated in vacuo, and the product extracted from theresulting residue with chloroform. The chloroform extract, after drying,crystallizes from acetone ether. M.P. 157- 163 C. Recrystallizationgives substantially pure product. M.P. 167-168" C.

rm 2.85-3.03 (OH), 6.026.17,u

The corresponding cis isomer is obtained by chromatography of the motherliquor of the crystallization of the trans isomer on alumlna and elutionof the alumina with a mixture of chloroform and benzene.

When other l-acyl derivatives of N-t-butyl-4-ketohexahydronicotinamidesuch as other l-lower alkanoyl derivatives, for example, thel-propionyl, l-valeryl, or the 1- hexyl derivative is reduced by theabove procedure, the corresponding 1-acyl-4-hydroxy compound isproduced.

EXAMPLE 4 Trans-N-t-butyl-1-acetyl-4-acetoxyhexahydronicotinamideApproximately 1.0 gram of trans-t-butyl-1-acety1-4-hydroxyhexahydronicotinamide is dissolved in 2.5 ml. of acetic anhydrideand 5 ml. of pyridine to produce trans-N-t-butyl-1-acetyl-4-acetoxyhexahydronicotinamide, which is obtained inquantitative yield on evaporation of the mixture of excess aceticanhydride and pyridine. M.P. 166 C.

Similarly, upon reaction with other lower alkanoyl anhydrides or a loweralkanoyl halide such as the chloride or bromide, the corresponding4-acyloxy compound is obtained.

EXAMPLE 5 Cis-N-t-butyl-1-acetyl-4 hydroxyhexahydronicotinamide Asolution of 961 mg. of N-t-butyl-1-acetyl-4-ketohexahydronicotinamide in20 ml. of methanol is mixed with a pre-reduced suspension of platinumoxide in 10 ml. of methanol and shaken in an atmosphere of hydrogen atatmospheric pressure to produce cis-N-t-butyl-1-acetyl-4-hydroxyhexahydronicotinamide in excellent yield. The catalyst is removedfrom the reaction mixture by filtration and the product is obtained fromthe filtrate as a residual clear, colorless oil after evaporation of themethanol.

Similarly, other l-acyl derivatives such as other 1- lower alkanoylcompounds can be reduced to produce the correspondingN-t-butyl-1-acyl-4-hydroxyhexahydronicotinamide.

EXAMPLE 6 Cis-N-t-butyl-1-acetyl-4-acetoxyhexahydronicotinamide Asolution of 740 mg. of cis-N-t-butyl-l-acetyl-4-hydroxyhexahydronicotinamide in 5 ml. of pyridine and 2.5 ml. of acetic anhydride is maintainedat room temperature for about 16 hours. The product,cis-N-t-butyl-l-acetyl-4-acetoxyhexahydronicotinamide, is produced insubstantially pure form by evaporation of the entire reaction mixtureunder reduced pressure and crystallization of the residue from a mixtureof acetone-ether, M.P. 184- 187 C.

In the same way, other 4-lower alkanoyloxy compounds can be producedusing other lower alkanoyl anhydrides.

EXAMPLE 7 N-t-butylnicotinamide A mixture of 800 mg. ofcis-N-t-butyl-1-acetyl-4-acetoxyhexahydronicotinamide, 800 mg. of 30%palladium on charcoal catalyst, and 50 ml. of decalin having a boilingpoint of 190-192 C. is maintained at the reflux temperature forapproximately 16 hours under a nitrogen atmosphere during which timehydrogen gas is evolved and the product, N-t-butylnicotinamide, isobtained. The entire reaction mixture is then diluted with methylenechloride and the palladium catalyst removed from the reaction mixture byfiltration. The filtrate is extracted with 2.5 N aqueous hydrochloricacid to remove the product and the acid extract then washed withmethylene chloride. The aqueous acidic solution of the product is thenmade alkaline with 2.5 N aqueous sodium hydroxide solution, saturatedwith salt, and the product extracted with methylene chloride. Theproduct is then obtained in substantially pure form from the driedmethylene chloride extract by concentration in vacuo. The crystallineresidue 7 obtained is recrystallized from acetone-ether-petroleumether.M.P. 8586 C.

The trans form of the starting material can be similarly dehydrogenatedto produce N-t-butylnicotinamide. In the same way, the cis and transforms of other lower alkanoyl esters can be converted to thenicotinamide derivative by the above-described procedure.

EXAMPLE 8 Nicotinamide N-t-butylnicotinamide (440 mg.) is added inportions to a stirred solution of ml. of concentrated sulfuric acid at 0C. After about /2 hour, complete solution is realized and the reactionmixture is allowed to warm to about 25 C. After 2 additional hours at 25C., the mixture is poured portionwise onto about ml. of crushed ice withstirring, made alkaline with sodium hydroxide, and extracted withchloroform. After drying over magnesium sulfate, the chloroform extractis concentrated to an oil from which the nicotinamide is crystallizedupon the addition of ether.

EXAMPLE 9 Preparation of l-acetylhexahydronicotinamideN-t-butyl-1-acetylhex-ahydronicotinamide (440' mg.) is added in portionsto a stirred solution of 10 ml. of concentrated sulfuric acid at 0 C.Complete solution is realized within /2 hour. The yellow reactionmixture is then allowed to warm to C. After 2 additional hours at 25 C.,the mixture is poured portionwise onto ca. 15 ml. of crushed ice wtihstirring, neutralized with aqueous sodium hydroxide to phenolphthalein,and concentrated in vacuo to dryness. Chloroform is added and theinorganic salts removed by filtration. The organic extract is dried overmagnesium sulfate and concentrated to afford 381 mg. of oil whichcrystallizes upon trituration with ether. First crop; 265 mg., M.P.140-141 C.;

kglglloroiorm 2 I 2.88, 2.94, 3.0, 3.14, 6.02, 6.15 second crop; 7 mg.M.P. 135139 C. Both crops show a single spot on paper(formamide-chloroform system). An analytical sample prepared byrecrystallization from acetone-ether melts at 141-142 C.

What is claimed is:

1. The process for producing nicotinamide which comprises the step of:

(a) contacting a l-lower alkanoy1-3-cyano-4-ketohexahydropyridine orl-lower alkanoyl-3-cyano-4-amino- 1,2,5,6-tetrahydropyridine in a strongacid reaction medium with a source of tertinary butyl ions to produceN-t-butyl-l-lower alkanoyl-4-ketohexahydronicotinamide;

(b) contacting said N-t-butyl-l-loweralkanoyl-4-ketohexahydronieotinamide with a reducing agent selected fromthe group consisting of alkali metal borohydrides or hydrogen in thepresence of a noble metal hydrogenation catalyst to produceN-t-butyl-l-lower alkanoyl-4-hydroxy hexahydronicotinamide;

(c) contacting said N-t-butyl-l-lower alkanoyl-4-hydroxyhexahydronicotinamide with a lower alkanoyl acylating agent to produceN-t-butyl-l-lower alkanoyl-4-lower alkanoyloxyhexahydronicotinamide;

(d) heating said N-t-butyl-l-loweralkanoyloxy-4-hydroxyhexahydronicotinamide at a temperature of between-300" C. in an inert solvent in the presence of pallidum, platinum,ruthenium, rhodium, asmium or iridium to produce N-t-butyl nicotinamideand (e) hydrolyzing said N-t-butyl nicotinamide to obtain nicotinamide.

2. The process which comprises contacting N-t-butyll-loweralkanoyl-4-lower alkanoyloxyhexahydronicotinamide with palladium,platinum, ruthenium, rhodium, asmium or iridium at a temperature ofbetween 100300 C. and in an inert solvent to produceN-t-butylnicotinamide.

3. The process of claim 2 wherein N-t-butyl-l-acetyl-4-acetoxyhexahydronicotinamide is reacted.

References Cited Kushner et al. Chemical Abstracts, vol. 43, Par. 5025-e(1949).

HENRY R. JILES, Primary Examiner.

ALAN I. ROTMAN, Assistant Examiner.

US. Cl. X.R

